The objective of this project is to develop an advanced, clinically applicable islet/stem cell encapsulation system for type 1 diabetes (T1D). Cell encapsulation and transplantation holds enormous potential to treat T1D. Islets of allo or xeno origin or stem cell-derived beta cells are encapsulated in a material or device that protects the cells from host immune rejection while allowing facile mass transfer to maintain their survival and function. Numerous research groups worldwide have made important progress, but clinical application of cell encapsulation has remained elusive, due in a large part to the lack of a translatable encapsulation system that meets the following basic but critical clinical needs: (1) It must be easy to handle, use and transplant so that the encapsulation causes no harm to cells and the transplantation is minimally invasive; (2) It must have sufficient biocompatibility (i.e. minimal or no formation of fibrosis), robust mechanical stability and facile mass transfer (e.g. large surface area, short diffusion distance and controllable permselectivity) so that the transplant can function for a long time, at least several months; (3) It must be convenient to retrieve so that it can be removed or replaced in the event of transplant failure or medical complications; (4) It must be scalable so that it can deliver sufficient cell mass to produce a therapeutic effect. To meet these needs, we propose to develop a novel, clinically translatable, TRAFFIC (Thread-Reinforced Alginate Fiber For Islet enCapsulation) system from our newly developed, non-fibrotic zwitterionic-alginates for T1D treatment. The critical innovations include both the structure design (i.e. incorporation a thin but tough polymer thread into the center of a hydrogel fiber along its axis) and the hydrogel chemistry (i.e. zwitterionically modified alginates). The inner polymer thread imparts mechanical robustness and enables easy handling, implantation and retrieval, while the outer zwitterionic- alginate hydrogel fiber provides necessary biocompatibility and facile mass transfer. We aim to achieve long-term (>6 months) cures of diabetic mice using both rat islets and stem cell-derived beta cells by optimizing the biocompatibility and mass transfer properties of the device. We will also scale up the device and demonstrate its retrievability and functionality in dogs. The anticipated outcome of this proposed research will be the development of a new cell encapsulation system that is translatable for T1D patients.